title: Downregulation of postsynaptic density-95-interacting regulator of spine morphogenesis reduces glutamate-induced excitotoxicity by differentially regulating glutamate receptors in rat cortical neurons.
abstract: Glutamate-induced excitotoxicity is involved in many neurological diseases. Preso, a novel postsynaptic scaffold protein, mediates excitatory synaptic transmission and various synaptic functions. In this study, we investigated the role of Preso in the regulation of glutamate-induced excitotoxicity in rat cortical neurons. Knockdown of Preso with small interfering RNA improved neuronal viability and attenuated the elevation of lactate dehydrogenase (LDH) release after glutamate treatment. Downregulation of Preso also inhibited an increase in the BAX/Bcl-2 ratio and cleavage of caspase-9 and caspase-3. Although the expression and distribution of metabotropic glutamate receptor (mGluR) 1/5, NR1, NR2A and NR2B were not changed by knockdown of Preso, downregulation of Preso protected neurons from glutamate-induced excitotoxicity by inhibiting mGluR and N-methyl-D-aspartate receptor function. However, downregulation of Preso neither affected the expression of GluR1 and GluR2 nor influenced the function of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor after glutamate treatment. Furthermore, intracellular Ca(2+) was an important downstream effector of Preso in the regulation of excitotoxicity. These results suggest that expression of Preso promotes the induction of excitotoxicity by facilitating different glutamate receptor signaling pathways. Therefore, Preso might be a potential pharmacological target for preventing and treating neurological diseases.
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Luo
authors.forename: Yuefan
authors.initials: Y
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Rao
authors.forename: Huan
authors.initials: H
authors.lastname: Bian
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Mengdong
authors.initials: M
authors.lastname: Liu
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shuhui
authors.initials: S
authors.lastname: Dai
authors.forename: Xu
authors.initials: X
authors.lastname: Yan
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019921:Biotinylation; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: C576234:FRMPD4 protein, rat; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D053148:Caspase 3; D053453:Caspase 9; D002118:Calcium
keywords: apoptosis; excitotoxicity; glutamate receptor; postsynaptic density; scaffold protein